Abstract
Genetic factors influence medication response (pharmacogenetics), affecting the pharmacodynamics and pharmacokinetics of many medicaments used in clinical care. The ability of medications to cross the blood–brain barrier (BBB) represents a critical putative factor in the effectiveness and tolerability of various medications relevant to central nervous system disorders (CNS), cancer, and broader medical conditions at a pharmacokinetic (dosing) level. Pharmacogenetics has the potential to personalise medicine to a greater extent than has been possible, with the potential to help reduce heuristic delays to effective tolerable pharmacotherapy. Here, we critically examine and summarise the evidence, particularly for ABCB1 polymorphisms associated with drug transportation and other clinical relevance. These transporters appear to have a role in BBB pharmacogenetics and may indicate new avenues of research that extend beyond the current paradigm of CYP450 polymorphisms. We identify some of the most promising variants for clinical translation while spotlighting the complexities of the involved systems and limitations of the current empirical literature.
Key Points
- Blood–Brain Barrier Function: The BBB regulates CNS access through tight endothelial junctions and active transport mechanisms, influencing drug permeability and therapeutic efficacy.
- Role of ABC Transporters: ATP-binding cassette (ABC) transporters, particularly ABCB1 (P-glycoprotein), play a critical role in drug efflux at the BBB, affecting drug bioavailability and resistance in cancer and CNS disorders.
- Genetic Variations in ABCB1: Polymorphisms such as rs2032582 and rs1045642 significantly impact P-glycoprotein function, altering drug efficacy, toxicity, and CNS penetration.
- Clinical Implications in Psychiatry: Pharmacogenetic insights into ABCB1 variants enable tailored treatment for psychiatric disorders like major depressive disorder (MDD) and schizophrenia by optimizing drug dosing and minimizing side effects.
- Applications in Oncology: Genetic variations in ABC transporters are associated with chemotherapy response and survival rates in cancers such as lung cancer and multiple myeloma, enabling personalized treatment strategies.
- Neurodegenerative Diseases: Pharmacogenetics has implications for diseases like Alzheimer’s, where drug transport across the BBB can influence therapeutic outcomes.
- Challenges in Translation: Variability in genetic impact across populations and the complex interplay of transporters and metabolic enzymes hinder the widespread adoption of pharmacogenetically guided therapies.
- Potential of Personalized Medicine: Integrating pharmacogenetic insights into clinical practice can reduce trial-and-error in drug selection and improve treatment efficacy, especially for CNS and oncology drugs.
- Emerging Research Areas: Investigating underexplored genetic variants and their roles in drug transport and metabolism may uncover new therapeutic targets and refine existing pharmacogenetic applications.
- Future Directions: Expanding high-quality, population-specific studies and incorporating pharmacogenetics into broader precision medicine frameworks will be essential for optimizing drug therapies and improving patient outcomes.
